A number of distinct stress signaling pathways in myocardium cause cardiac hypertrophy and heart failure. Class II histone deacetylases (HDACs) antagonize several stress-induced pathways and hypertrophy. However, cardiac hypertrophy induced by transgenic over-expression of the homeodomain only protein, HOP, can be prevented by the non-specific HDAC inhibitors trichostatin A (TSA) and valproic acid (VAL), suggesting that alternate targets that oppose class II HDAC function might exist in myocardium. We tested the effects of class I-HDAC selective inhibitor, SK-7041 (SK), on cardiac hypertrophy induced by aortic banding (AB). Cardiac hypertrophy induced by AB for 2 weeks were significantly reduced by simultaneous administration of SK. Echocardiogram revealed that exaggerated left ventricular systolic dimensions were relieved by SK. SK inhibited atrial natriuretic factor (ANF) expression by repressing its promoter activity in primarily cultured rat neonatal cardiomyocytes or in H9c2 cardiomyoblast cell lines, while it activated the promoter activity in 293T cells. Promoter mapping analysis revealed that SK-responsive element exists in -105 bp upstream region of transcription start site of ANF promoter. These results suggest that the class I HDAC mediates cardiac hypertrophy by repressing the promoter activity of gene expression in fetal gene program.